The present invention relates to an improved method of making drug delivery devices for the controlled release of pharmacologically active agents and further, to drug delivery devices made by such method. More specifically, the present invention relates to a method of forming a film comprising one or more biodegradable polymeric materials, one or more pharmacologically active agents, and one or more biocompatible solvents. The film is then partially dried, rolled or otherwise shaped, and then compressed. In this manner, the amount of pharmacologically active agent(s) that can be incorporated into the drug delivery device is increased and the pharmacologically active agent(s) is/are substantially homogeneously distributed throughout the drug delivery device. As a result, the release characteristics of the pharmacologically active agent from the drug delivery device are enhanced.
Systemic delivery, e.g., as by inhalation or ingestion, of pharmacologically active agents, although an effective and easily managed mode of administration, is less than adequate for some treatment applications. For example, some pharmacologically active agents are poorly absorbed from the blood stream, or alternatively, irritate the stomach lining. Thus, in some instances, local delivery of pharmacologically active agents is desirable.
For example, local delivery of pharmacologically active agents to peripheral nerves is often times desirable for the management of acute and chronic pain. However, local delivery of pharmacologically active agents to peripheral nerves is currently primarily performed by bolus injections or by the insertion of an infusion catheter. Although bolus injections are generally a safe and efficacious form of treatment, this mode of local delivery can be limited by the volume of liquid that can be injected, the maximal non-toxic concentration of the pharmacologically active agent that can be administered, and the system toxicity levels that can ensue subsequent to absorption and circulation to other body organs. Furthermore, inasmuch as delivery via an infusion catheter requires monitoring to initially place the catheter, and continually thereafter to ensure that the catheter does not migrate, this mode of local delivery is also suboptimal. Thus, alternative methods of localized drug delivery would be desirable.
In efforts to address this need, many implantable drug delivery devices have been developed over the past several years. Such drug delivery devices may be formulated from synthetic or natural, biodegradable or non-biodegradable, polymers. Biodegradable polymers are preferred since these materials gradually degrade in vivo over time, e.g., by enzymatic or non-enzymatic hydrolysis, when placed in an aqueous, physiological environment. Thus, the use of biodegradable polymers in drug delivery devices is preferred since their use avoids the necessary removal of the drug delivery device at the end of the release period.
Hydrogel-forming polymeric materials, in particular, have been found to be useful in the formulation of drug delivery devices. See, e.g., Lee, J. Controlled Release, 2, 277 (1985). Hydrogel-forming polymers are polymers that are capable of absorbing a substantial amount of water to form elastic or inelastic gels. Many non-toxic hydrogel-forming polymers are known and are easy to formulate. Furthermore, drug delivery devices incorporating hydrogel-forming polymers offer the flexibility of being capable of being implantable in liquid or gelled form. Once implanted, the hydrogel forming polymer absorbs water and swells. The release of a pharmacologically active agent incorporated into the device takes place through this gelled matrix via a diffusion mechanism.
However, many hydrogels, although biocompatible, are not biodegradable. Furthermore, most drug delivery devices comprising hydrogels require the use of undesirable organic solvents for their manufacture. Residual amounts of such solvents could potentially remain in the drug delivery device, where they could cause solvent-induced toxicity in surrounding tissues or cause structural or pharmacological degradation to the pharmacologically active agents incorporated within the drug delivery device. Finally, implanted drug delivery devices in general, and implanted drug delivery devices comprising hydrogel-forming polymers in particular, oftentimes provide suboptimal release characteristics of the drug(s) incorporated therein. That is, typically, the release of pharmacologically active agents from an implanted drug delivery device is irregular, e.g., there is an initial burst period when the drug is released primarily from the surface of the device, followed by a second period during which little or no drug is released, and a third period during which most of the remainder of the drug is released.
Thus, it would be desirable to provide improved drug delivery devices capable of sustained, controlled local delivery of pharmacologically active agents when implanted while also being biodegradable and resorbable such that removal of the device is not necessary. It would further be desirable to control the rate of delivery from such devices to avoid possible side effects associated with irregular delivery, e.g., high drug concentration induced tissue toxicity. Finally, it would be advantageous if such devices could be manufactured with biocompatible solvents so that the potential for residual solvent toxicity is reduced.
The present invention relates to an improved method of manufacturing drug delivery devices and further, to drug delivery devices made by such method. More specifically, the method of the present invention comprises combining one or more biodegradable polymeric materials, one or more pharmacologically active agents, and at least one biocompatible solvent to form a coatable composition. This composition is then coated so as to form a film (preferably a substantially planar body having opposed major surfaces and preferably having a thickness between the major surfaces of from about 0.1 millimeters to about 5 millimeters) that is subsequently at least partially dried until the film is cohesive, formed (rolled, folded, accordion-pleated, crumpled, or otherwise shaped) into a cohesive body having a surface area less than that of the film, and then compressed to provide a drug delivery device in accordance with the present invention. Drug delivery devices made utilizing the method of the present invention are capable of the sustainable, controllable local delivery of pharmacologically active agent(s), while also providing the advantage of being capable of being degraded, and preferably safely resorbed, thereby eliminating the need for the removal of the drug delivery device.
Thus, in one aspect, the present invention provides an improved method of making drug delivery devices. Specifically, the method comprises the steps of preparing a coatable composition comprising one or more biodegradable polymeric materials, one or more pharmacologically active agents, and one or more biocompatible solvents. Preferably, the biocompatible solvent is water, dimethyl sulfoxide (DMSO), ethanol, an oil, combinations of these, or the like. More preferably, the biocompatible solvent comprises water. The coatable composition is then coated to form a film and dried until the coated film can be formed into a cohesive body, e.g., preferably until the film has a solvent content of from about 50% to about 70%. The film is then formed into the cohesive body, preferably with a surface area less than that of the film. The film is then shaped into a cohesive body, e.g., rolled, folded, accordion-pleated, crumpled, or otherwise shaped into a cylinder or shaped into a ball, cube and the like, preferably with a surface area less than that of the film. The cohesive body is then compressed to remove as much of the solvent as possible so that the compressed body remains cohesive, but without removing so much solvent that the compressed body becomes brittle or otherwise lacks cohesiveness. Typically, the resulting drug delivery device has a solvent content of from about 30% to about 60%, preferably from about 40% to about 50%.
It has now been discovered that, by coating the aforementioned components into a film, partially drying the film, forming the film into a cohesive body and subsequently compressing the cohesive body, that a drug delivery device is provided with a substantially homogeneous distribution of the pharmacologically active agent(s). Due to this substantially homogeneous distribution and also to the fact that the device degrades over time, the drug delivery device of the present invention provides a sustainable and controllable release of the pharmacologically active agent(s). Furthermore, the method of the present invention utilizes biodegradable, and preferably resorbable, polymeric materials. As a result, a drug delivery device formed in accordance with the method of the present invention does not have to be removed once inserted or implanted. Finally, the method of the present invention utilizes biocompatible solvents. As such, any solvent remaining in the drug delivery device after the manufacture thereof presents a reduced, if not substantially eliminated, risk of producing undesirable side effects when implanted into a patient.
Thus, in another aspect, the present invention provides a drug delivery device made in accordance with the method of the present invention. Preferably, the biodegradable polymeric material incorporated into a device in accordance with the present invention comprises a biodegradable protein, more preferably, a water-absorbing, biodegradable protein, most preferably, a genetically engineered, water-absorbing, biodegradable protein comprising silklike blocks and elastinlike blocks. The drug delivery device can incorporate any desired pharmacologically active agent or even a second drug delivery device, e.g., corticosteroids, opioid analgesics, neurotoxins, local anesthetics, vesicles, lipospheres, microspheres, enzymes, combinations of these, and the like.
It has now additionally been discovered that the sustainable release and rate controllable characteristics of the present drug delivery device may also been beneficially utilized to deliver other drug delivery devices that are either vulnerable to migration from the delivery site and/or are potentially undesirably reactive with surrounding bodily fluids or tissues. That is, not only can the drug delivery device of the present invention be beneficially utilized to deliver a pharmacologically active agent to a particular site where a therapeutic effect is desired, but also the drug delivery device of the present invention may be a xe2x80x9ctwo-stage drug delivery devicexe2x80x9d utilized to deliver a second, migration-vulnerable drug delivery device comprising a pharmacologically active agent so that the second, migration-vulnerable and/or reactive drug delivery device is held in place, e.g., by the gelled matrix provided by the drug delivery device of the present invention. In the instance that the two-stage drug delivery device is used to deliver a reactive drug delivery device, the gelled matrix of the two stage drug delivery device reduces, if not substantially prevents the second drug delivery device from undesirably reacting with surrounding bodily tissues and/or fluids.
Thus, in another aspect, the present invention provides a drug delivery device comprising a compressed matrix comprising at least one biodegradable polymeric material and at least one such substance vulnerable to migration and/or reaction with surrounding tissues or bodily fluids, wherein said substance is substantially homogeneously distributed within the matrix. Examples of such substances include, but are not limited to, vesicles, such as lipospheres or liposomes, comprising an encapsulated pharmacologically active agent, microspheres comprising an encapsulated pharmacologically active agent, combinations of these, and the like.
Inasmuch as the drug delivery devices of the present invention provide the sustained release of pharmacologically active agents in a rate controllable fashion, are capable of delivering other migration-vulnerable and/or reactive drug delivery devices and furthermore are produced in a manner that reduces, if not eliminates, the risk of residual solvent toxicity, there is also provided in accordance with the present invention a method of effecting a local therapeutic response in a patient in need of such treatment. Specifically, the method comprises the step of delivering a drug delivery device in accordance with the present invention to the site at which a local therapeutic response is desired. Preferably, the therapeutic response effected is an analgesic response, an antiinflammatory response, an anesthetic response, a response preventative of an immunogenic response, combinations of these, and the like.
As used herein, unless stated otherwise, all percentages are percentages based upon the weight of the biodegradable polymeric material.